Mental health and cognition in relation to adherence to antiretroviral therapy among people living with HIV in Kazakhstan: a cross‐sectional study

Abstract Introduction There is a research gap in how mental health and cognition are associated with antiretroviral treatment (ART) adherence among people living with HIV (PLWH) in Kazakhstan. Methods We randomly selected and enrolled 230 PLWH from the Almaty City AIDS Center registry (June−November 2019) into a cross‐sectional study. We examined associations between self‐reported ART adherence for the last 1 and 2 weeks; the Adherence Self‐Efficacy Scale (ASES) and symptoms of depression (Patient Health Questionnaire‐9 [PHQ‐9]), anxiety (Generalized Anxiety Disorder tool [GAD‐7]), post‐traumatic stress disorder (PTSD Checklist [PTSD]); cognitive function (PROMIS v2.0 Adult Cognitive Function 8a short form) and forgetfulness (Forgetfulness Assessment Inventory). We used cut points of ≥5 for at least mild and ≥10 for at least moderate symptom severity for PHQ‐9 and GAD‐7 and of ≥44 for PTSD. Logistic and linear regression analyses were used. Results Participants’ median age was 40.0 (IQR: 34−47) with 40.9% (n = 94) of females in the sample. Those who missed at least one pill for the last 2 weeks had higher odds of reporting at least mild depression (aOR = 3.34, 95% CI: 1.22–9.11, p < 0.05); mild anxiety (aOR = 3.27, 95% CI: 1.20–8.92, p < 0.05); and PTSD (aOR = 4.04, 95% CI: 1.15–14.21, p < 0.05) symptoms. Participants who missed at least one pill for the last week had higher odds of at least mild depression (aOR = 7.74, 95% CI: 1.31–45.7, p < 0.05), moderate anxiety (aOR = 21.33, 95% CI: 3.24–140.33, p < 0.005) and PTSD (aOR = 13.81, 95% CI: 2.36–80.84, p < 0.005) symptoms. Participants with better cognitive function had lower odds of non‐adherence over the last week (aOR = 0.88, 95% CI: 0.81–0.96, p < 0.005) and higher ASES scores (β = 0.26, 95% CI: 0.13–0.40, p < 0.005). Poor memory was associated with higher odds of non‐adherence over the last week (aOR = 4.64, 95% CI: 1.76–12.24, p < 0.005) and lower ASES score (β = −0.31, 95% CI: −0.45 to 0.16, p < 0.005). Those who had at least mild depression (β = −0.21, 95% CI: −0.35 to −0.07, p < 0.005); moderate anxiety (β = −0.21, 95% CI: −0.34 to −0.07, p < 0.005) and PTSD (β = −0.19, 95% CI: −0.33 to −0.05, p < 0.005) symptoms had lower ASES scores. Conclusions Depression, anxiety and PTSD symptoms, poorer cognition, and forgetfulness were associated with poorer ART adherence and worse adherence self‐efficacy. It is crucial to assess and treat mental illness and provide support for PLWH with worsened cognition to enhance ART adherence.


I N T R O D U C T I O N
Eastern Europe and central Asia (EECA), including Kazakhstan [1], is the only region with a rising HIV incidence, with an estimated 33,000 people living with HIV (PLWH).Of these, 80% knew their HIV status, 64% received antiretroviral treatment (ART) and 55% had a viral load of <1000 copies/ml [2].
Published literature indicates that ART adherence is associated with mental health and cognitive function among PLWH globally.However, there is limited data on associations of ART adherence and ART self-efficacy with mental health symptoms and cognition among PLWH in Kazakhstan.We hypothesized that symptoms of depression, anxiety and posttraumatic stress disorder (PTSD) as well as poorer cognition, are associated with poorer ART adherence and lower ART self-efficacy.In this cross-sectional study, we examined the association of ART adherence and ART self-efficacy with depression symptoms, anxiety symptoms, clinically relevant PTSD and cognitive function among PLWH in Almaty, Kazakhstan.

M E T H O D S
This cross-sectional study took place in Almaty, Kazakhstan.
In Kazakhstan, all HIV-related services (testing, treatment and prevention) are provided by AIDS centres.The Almaty AIDS City Center is the only healthcare facility that provides HIVrelated services for PLWH in Almaty.Eligibility criteria were: (1) 18 years old or older; and (2) prescribed ART for at least 6 months.PLWH were excluded if they (1) showed evidence of very severe psychiatric or cognitive impairment or (2) were not fluent in Russian.We randomly selected 246 participants from the Almaty AIDS City Center roster and 230 were successfully enrolled in the study between June and November 2019.Each participant signed a consent form and received compensation (∼USD$10) for a 90-minute computerized selfassisted interview.The interview was monitored by a trained psychologist, who also provided a consultation and referral for treatment.A nurse extracted clinical data from the medical records of participants.We were unable to utilize CD4 + cell count and HIV viral load because laboratory tests were collected across wide time intervals (every 6 months), which did not align with survey dates.All data were collected using surveys.

Ethical approvals
The study obtained ethical approvals from the Al-Farabi Kazakh National University Ethics Committee and the Columbia University Institutional Review Board.

Dependent variables
Self-reported ART adherence.Self-reported ART adherence was determined by answering the question: "When was the last time you missed taking any of your antiretroviral medications?"Response options were: "last 3 days," "within the past week," "1−2 weeks ago," "2−4 weeks ago," "3 months ago," "more than 3 months ago," "never skip medications."Adults who reported (1) missing at least one pill in the last week and (2) missing at least one pill in the last 2 weeks were defined as two categories of ART non-adherent participants, while those who did not miss any pills in these time periods were defined as ART adherent.Adherence self-efficacy.The 12-item Adherence Self-Efficacy Scale (ASES) was used to assess PLWH's adherence selfefficacy [39].Responses range from 1 (cannot do it at all) to 10 (certainly can do it).Item scores were averaged for each respondent, with higher scores indicating higher adherence self-efficacy [39].The overall score ranged from 0 to 120.Cronbach's alpha in our sample was α = 0.97.Independent variables.Socio-demographic variables included age, gender, employment status, marital status, ethnicity, history of ever being diagnosed with infectious diseases, selfreported history of ever being diagnosed with any mental illness and education level.Substance use variables included injection drug use ever in a lifetime (yes/no) and hazardous alcohol drinking, assessed by the Alcohol Use Disorders Identification Test (AUDIT).A score of ≥8 is considered hazardous drinking [35].The Cronbach's alpha in our sample was α = 0.879505.Mental health measures.To evaluate depressive symptoms, we used the Patient Health Questionnaire-9 (PHQ-9) [40], with a total score range of 0−27.Scores of 0−4, 5−9, 10−14, 15−19 and 20−27 represent cut points for no, mild, moderate, moderately severe and severe depression, respectively.We used cut points of ≥5 for at least mild and ≥10 for at least moderate depression symptom severity [41].The Cronbach's alpha in our sample was α = 0.90.
The Generalized Anxiety Disorder (GAD-7) instrument was used [42], with a score range of 0−21.Scores of 0−4, 5−9, 10−14 and 15−21 represent ranges for minimal, mild, moderate and severe anxiety, respectively.We used cut points of ≥5 for at least mild and ≥10 for at least moderate anxiety symptoms severity.The Cronbach's alpha in our sample was α = 0.92.
The PTSD Checklist (PCL) was used to measure PTSD: a 17-item self-report questionnaire (score range 17−74) [43,44].A score of ≥44 is considered to be clinically relevant PTSD.The Cronbach's alpha in our sample was α = 0.96.

2.3
Cognitive measures PROMIS v2.0 Adult Cognitive Function 8a short form (8-item) was used to assess cognitive function [45].The PROMIS v2.0 assesses the frequency of cognitive difficulties experienced in the past 7 days based on self-report.Lower raw scores on the PROMIS v2.0 indicate greater subjective cognitive difficulty [46].The total raw score ranges from 8 to 40.The Cronbach's alpha in our sample was α = 0.96.The 16-item Forgetfulness Assessment Inventory was used to assess subjective memory over the past 4 weeks.A higher score corresponds to more forgetfulness or poorer memory [47].Responses were recorded on a 5-point Likert scale.The overall score ranges from 0 to 5 [47].Cronbach's alpha in our sample was α = 0.95.

Data analysis
Descriptive statistics were used to summarize participant characteristics for history of mental illness and sociodemographic variables.The median and interquartile range (IQR) for continuous variables were calculated for the total sample and by the self-reported history of ever being diagnosed with any mental illness.Percentages of participants who screened positive for mental health symptoms were calculated based on clinically relevant cut-points of the PHQ-9 score for depression symptoms, including at least mild (score ≥5) and at least moderate symptoms (score ≥10); cut-points of the GAD-7 screening instruments, for at least mild (score ≥5) and moderate (score ≥10) anxiety symptoms; and cut-point of PCL (score ≥44) for clinically relevant PTSD.
We employed multivariable regression analyses to address two self-reported dependent variables: ART adherence and ASES score.For each primary independent variable: clinically relevant depression symptoms, anxiety symptoms, clinically relevant PTSD, cognitive function and forgetfulness, we used logistic regression analyses to calculate crude odds ratios (OR) and 95% confidence intervals (95% CI) to evaluate associations of self-reported ART non-adherence: missed at least one pill in the last 2 weeks and missed at least one pill in the last week separately.For each primary independent variable, we conducted multivariable logistic regression analyses, adjusting for age, sex, education, employment, injection drug use and hazardous drinking.
The second dependent variable was the continuous ASES score.Linear regression analyses were used to calculate crude standardized regression coefficients (β) with 95% CI to predict the ASES score by each primary independent variable.Then, multivariable standardized regression coefficients (β) with 95% CI were calculated separately for each independent variable adjusted for age, gender, education, employment, injection drug use and hazardous drinking.All analyses were conducted using SAS statistical software version 9.4.

Sample characteristics
Table 1 shows the demographic, clinical and other characteristics, including adherence to ART, ASES scale, mental health symptoms, cognitive function score and forgetfulness score of the sample stratified by self-reported mental health illness ever diagnosed in their lifetime.

Associations of ART adherence with depression symptoms, anxiety symptoms, clinically relevant PTSD and cognitive function
Multivariable logistic regression analyses showed that mental health symptoms were associated with a higher probability of non-adherence to ART (Table 2).Those who missed at least one pill in the last 2 weeks had higher odds of reporting mild (aOR = 3.34, 95% CI: 1. 22 Participants with better cognitive function had lower odds of non-adherence in the last week (aOR = 0.88, 95% CI: 0.81-0.96,p < 0.005).Having more forgetfulness was associated with higher odds of non-adherence in the last week (aOR = 4.64, 95% CI: 1.76-12.24,p < 0.005) (Table 2).
Participants with better cognitive function had higher ASES scores (β = 0.26, 95% CI: 0.13-0.40,p < 0.005).A higher forgetfulness score, denoting poorer memory, was associated with a lower ASES score (β = −0.31,95% CI: −0.45 to −0.16, p < 0.005) (Table 3).There are multiple studies demonstrating that HIV is linked to an increased likelihood of cognitive impairment due to the underlying pathophysiology of HIV [31-35, 50, 54].On the other hand, long-term exposure to ART medications can be associated with neurocognitive impairment [55,56].The neurotoxic and neuropsychiatric impacts stemming from both the ART and the HIV infection itself necessitate a more comprehensive grasp of the pathological, pharmacological and behavioural mechanisms involved into the worsening of the cognitive function of PLWH [57][58][59][60].

D I S C U S S I O N
This study has several limitations.First, as a cross-sectional study, we cannot determine the causality of relationships between mental health, cognitive function and ART adherence.Second, due to social desirability bias, participants may have overreported adherence to ART and overrated cognitive   function and may have provided socially acceptable answers [61].Third, as noted above, we did not have concurrent data on CD4 + cell count and HIV viral load.In addition, while Tscores for PROMISv2, our cognitive function assessment, exist for the US general population, we did not convert our raw scores to T-scores for these analyses since they may not be representative of PLWH in Kazakhstan.PROMISv2 T-scores do not exist for the Kazakh population [62].However, this study had several strengths that address some limitations in prior research including the use of a random sample from a roster of PLWH patients at the largest city AIDS Center, high participation rates and the use of validated scales of mental health and cognitive function with good reliability.
Research showed that PLWH can benefit from a wide range of mental health interventions [63].These four models are suggested to be promising strategies for delivering efficient and effective mental healthcare in resource-constrained settings: task shifting, stepped care, trans-diagnostic approaches and technology-based interventions [63,64].Routine screenings for mental health issues [65,66] integrated into the HIV care continuum with mental health counselling shifting from specialized to non-specialized health workers or trained lay persons are promising intervention approaches [67][68][69].Clinicians have to be able to screen for mental health disorders and access cognitive function to refer for treatments [63] and provide support for patients with worsened cogni-  tive function to improve their ART adherence [22,[70][71][72][73][74][75][76].
Technology-based approaches including digitalized interventions that can be delivered via applications on smartphone or other devices can be effective way to support PLWH with mental illness or/and worsened cognition [77,78].

C O N C L U S I O N S
The findings emphasize the vital importance of incorporating mental health and cognitive function assessments into HIV treatment programmes.This approach is essential due to the observed links between mental health issues and diminished cognitive abilities, including forgetfulness, and their correlation with reduced adherence to ART and lower self-efficacy in treatment adherence.Strengthening mental health support and focusing on the cognitive function within these programmes can significantly enhance the adherence and overall wellbeing of PLWH.

C O M P E T I N G I N T E R E S T S
The authors declare no competing interests.

A U T H O R S ' C O N T R I B U T I O N S
GM and AD collaborated on drafting the manuscript.JD, NE-B, LG, DG, SLR, ANP, AT and SP contributed to revisions of manuscript drafts.GM, JD, AD and ANP contributed to outlining the research objectives, sampling design and data analysis.GM and AD contributed to data analysis.JD, DG, LG, NE, AT, SP, ZN, ANP and AYD contributed substantially to the conception and design of the work and interpretation of results.AYD contributed to data collection.All authors had final approval of the version to be published and agreed to be accountable for all aspects of the work.

A C K N O W L E D G E M E N T S
We thank the participants, research assistants, nurses, psychologist and administration staff of Almaty City AIDS Center.

F U N D I N G
This study was supported by the Fogarty International Center and the National Institute of Drug Abuse under Award Number D43 TW010046.PIs: Drs.Jack DeHovitz & Zhamilya Nugmanova.

D ATA AVA I L A B I L I T Y S TAT E M E N T
Data are available on request from the authors.
a Fisher.b Wilcoxon.c